The present invention relates to a drug for the prophylaxis and therapy of the diseases associated with ocular fundus tissue cytopathy.
The ocular fundus tissue comprises the retina, retinal vessels, retinal pigment epithelium, optic disc, choroid, and sclera and constitutes an organ for transmitting light stimuli from the crystalline lens to the brain through optic nerve cells. Therefore, injury of the ocular fundus tissue cells induces serious diseases leading to blindness in many cases. Impairment of ocular fundus tissue cells is frequently caused by ischemia and changes of various biological substances, such as elevation of excitatory amino acid levels and decreases in ATP. Moreover, the ocular fundus tissue cells are damaged by systemic diseases such as hypertension and diabetes, aging, and trauma as well. While laser photocoagulation is used for inhibition or elimination of neogenetic vessels in diabetic retinopathy and macular degeneration, elimination of vessel occlusion in retinal vessel occlusion, and the like, ocular fundus tissue cytopathy caused by changes in the circulation in the vicinity of the laser irradiation site, inflammatory reaction due to the heat of photocoagulation and the like poses problems.
The diseases associated with ocular fundus tissue injuries develop due to the various factors mentioned above or a complicated combination of various factors. The disease arising from injuries to the ocular fundus tissue includes retinochoroidal disease (e.g. retinal vascular abnormalities such as retinal vessel occlusion, retinal periphlebitis, Eales"" disease, ischemic eye syndrome, retinal arteriolar macroaneurysm, etc.; retinopathy associated with hypertension or renal disease; diabetic retinopathy; retinal pigment epithelitis; retinal dystrophy; macular dystrophy; retinochoroidal atrophy; retinochoroiditis; macular degeneration; macular edema; retinal pigment epithelial detachment; retinal detachment; degenerative retinoschisis; tumors such as retinoblastoma, tumors of the retinal pigment epithelium, capillary hemangioma of the optic nerve head, etc.; optic neuropathies such as ischemic optic neuropathy etc.; optic disc swelling such as choked disc/papilledema etc.); and glaucoma associated with ocular fundus tissue cytopathy (e.g. open angle glaucoma, low tension glaucoma, angle closure glaucoma, etc.); and further the posterior complications arising from photocoagulation such as macular edema, retinal detachment, optic neuritis, abnormal visual field, abnormal light sense, and color vision defect. As used herein, by the posterior complications arising from photocoagulation is meant ocular fundus tissue cytopathy, caused by changes in the circulation in the vicinity of laser irradiation site, which is attributable to photocoagulation upon laser irradiation, inflammatory reaction due to the heat of photocoagulation, and diseases induced by these disorders.
As the current drug therapy of diseases associated with ocular fundus tissue cytopathy, microcirculation improving agents such as tocopherol nicotinate, which is a vitamin E preparation, pentoxifylline, etc., various steroidal drugs, antiprostaglandins, and antiphologistic enzyme preparations are administered orally. However, those therapies are either not effective enough or have side-effect problems such as hypotension and gastrointestinal disorders. As therapeutic modalities for glaucoma, cholinergic agonists represented by pilocarpine, sympathomimetic drugs such as epinephrine, dipivefrin, etc., and xcex2-adrenergic antagonists such as timolol, pindolol, carteolol, etc. are available for topical administration (e.g. eye-drops) but various side effects associated with their mechanisms of action are problems.
Recently, it has been reported that compounds having calpain inhibitory activity have an action to inhibit ischemic cell death [Lee K., Frank S., Vanderklish, P., Arai A., Lynch G., Proc. Natl. Acad. Sci., 88, 7233-7237 (1991), Rami A., Krieglstein J., Brain Res., 609, 67-70 (1993)]. However, those reports describe only the inhibitory effect on cell death in connection with the death of neurons in the hypocampus and do not indicate the inhibitory effect of the drugs on ocular fundus tissue cytopathy or their utility in the field of ophthalmology. Moreover, the inhibitors so far used have many shortcomings in the aspect of transfer to tissues and adverse reactions. EP0771565 states that a cysteine protease inhibitor is useful for neovascularization in diabetic retinopathy etc. but does not even hint at diseases associated with ocular fundus tissue cytopathy.
The present invention has for its object provision of a drug for the prophylaxis and therapy of ocular fundus tissue cytopathy, which overcomes the above-mentioned disadvantages. It is a further object of the present invention to provide a drug for the prophylaxis and therapy of diseases arising from ocular fundus tissue cytopathy and a method for the prevention and treatment of such diseases.
It should be understood that, in the context of the present invention, the term xe2x80x9cocular fundus tissuexe2x80x9d means to include the retina, retinal blood vessels, retinal pigment epithelium, optic disc, choroid, sclera, and vitreous base, and that, of these tissues, the retina, retinal blood vessels, retinal pigment epithelium, optic disc, and choroid are sometimes referred to collectively as the retinochoroid.
The inventors of the present invention endeavored to develop a drug for the prophylaxis and therapy of ocular fundus tissue cytopathy, which is effective for improving ocular fundus tissue cytopathy and which is safe, and found that a compound of the following formula (I) 
wherein R1 represents an alkyl group having 1-4 carbon atoms or an aryl group having 6-10 carbon atoms which is optionally substituted; R2 and R3 may be the same or different and each represents hydrogen or an alkyl group having 1-4 carbon atoms or R2 and R3 may jointly form a ring having 3-7 carbon atoms; R4 represents a lower alkyl group which is optionally substituted by aryl, cycloalkyl, or aromatic heterocyclic residue, and a pharmaceutically acceptable salt thereof exhibit remarkable prophylactic or therapeutic efficacy against ocular fundus tissue cytopathy.